DESCRIPTION (adapted from applicant abstract): It is generally agreed that neurotrophic factors can protect neurons from insult, facilitate their recovery, and mediate several types of activity-dependent plasticity. Neurotrophic factors are regulated by neuronal activity, and certain types of behavior may impact their expression. Exercise is a type of behavior known to be good for health. Recently, the applicants investigated the possibility that exercise influences the expression of brain-derived neurotrophic factor (BDNF). The home cages of rats were equipped with running wheels to provide a means of voluntary exercise. Rats like to run, and after several nights with running wheels, adopt a consistent level of nightly running activity. The investigators found that levels of BDNF mRNA were increased after 2 nights of running and remained elevated, or continued to rise, depending on the brain region examined, through 7 nights. In the hippocampal subfield CA1, levels were elevated 94% over controls after 7 nights. They propose to expand these initial findings. They will determine the time in the circadian running cycle when this response is greatest, and explore in detail the time course of responses over a 3 month period. They will investigate whether the trk B receptor for BDNF, is similarly influenced. The regulation of growth factors may be especially important during aging. Accordingly, they will analyze the response of the aged brain to short-term exercise. In addition, they will explore the mechanism driving gene regulation in vivo to evaluate the significance of this response and to predict other responsive genes. Specifically, they propose that cholinergic activation is a major factor involved in the induction because BDNF can be regulated by this neurotransmitter and because cholinergic activation, expressed as the theta rhythm, is increased in the hippocampus during voluntary motor activity. Experiments to test this hypotheses will be carried out in vivo and in vitro on hippocampal cultures. Data from the proposed experiments will provide an initial characterization of how a simple, widely practiced activity impacts molecules known to be important for brain health.